Chronic HBV infection affects 1.5 million Americans, with Asian Americans, disproportionately affected, and =5000 deaths occur annually due to cirrhosis and liver cancer. With the availability of effective and well-tolerated HBV treatments, reductions in liver-related deaths are achievable, but unanswered questions regarding treatment include whether the current target groups for treatment should be expanded, if combinations of drugs are superior to single drug therapy, and what treatment endpoints should be used. In conjunction with the other HBV Clinical Trial Network investigators, the San Francisco HBV Consortium, a collaborative group of San Francisco investigators at the University of California San Francisco Medical Center, California Pacific Medical Center and UCSF/San Francisco General Hospital with access to >6000 persons with chronic HBV infection, will address key issues in the natural history, pathogenesis and treatment of chronic hepatitis B (CHB). With other HBV CRN investigators, we will establish an informational database of ~3000 persons with CHB for cross-sectional and cohort studies linked with a serum and tissue repository for clinical/translational studies. Our study aims for the database focus on (i) immune-tolerant CHB and the viral, genetic and host predictors of lost tolerance; and (iii) the risk of perinatal transmission in HBsAg-positive women. Each of these special populations is a potential target group for therapeutic studies within the Network. Additionally, we will also execute 2 clinical trials, with the primary goal of comparing combination versus monotherapy as first-line therapy for HBeAg-positive CHB and HBeAg-negative CHB. Combination therapy may offer greater antiviral potency and lower risk of drug resistance, but has added cost and may lower adherence. A clinical adaptive design is used. For HBeAg-negative CHB, we will compare entecavir (ETV) plus tenofovir (TDV) to tenofovir (TDV) and entecavir (ETV) monotherapies for a prolonged but finite treatment period of 48 months. For HBeAg-positive CHB, we will compare TDV monotherapy for48 months versus sequential TDV (for 3 month lead-in)/peginterferon (peg-IFN) alfa 2a for 6months/TDV for 39 months versus combination TDV plus ETV for 48 months. Patients with primary non-response or suboptimal virologic response at 6 and 24 months respectively, will be discontinued from treatment. HBeAg-positive CHB patients achieving HBeAg seroconversion will undergo randomized to 6 versus 24 months of consolidation TDV therapy. Host, genetic (including transporter polymorphisms), and virologic (HBsAg quantitation, cccDNA) will be examined as predictors of response/non-response.